WO2005003127A1 - Derives heteroaromatiques bicycliques en tant que modulateurs de la fonction cxcr3 - Google Patents

Derives heteroaromatiques bicycliques en tant que modulateurs de la fonction cxcr3 Download PDF

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WO2005003127A1
WO2005003127A1 PCT/GB2004/002735 GB2004002735W WO2005003127A1 WO 2005003127 A1 WO2005003127 A1 WO 2005003127A1 GB 2004002735 W GB2004002735 W GB 2004002735W WO 2005003127 A1 WO2005003127 A1 WO 2005003127A1
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group
optionally substituted
atom
alk
formula
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David Alan Owen
Robert John Watson
Johannes Wilhelm Georg Meissner
Daniel Rees Allen
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Celltech R & D Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a series of bicyclic heteroaromatic derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
  • chemokines chemotactic cytokines
  • eosinophils in the tissue eosinophilia that is a feature of a number of pathological conditions including asthma, rhinitis, eczema and parasitic infections.
  • chemokines have been implicated in a variety of autoimmune diseases, such as rheumatoid arthritis, irritable bowel disease and multiple sclerosis, as well as playing a critical role in the pathway of viral infection, such as invasion by HIV [Schwarz, M. K. and Wells, T. N. C, Curr. Opin. Chem. Biol., 1999, 3, 407-17; Bousquet, J. et al., N. Eng. J. Med., 1990, 323, 1033-39; Kay, A. B. and Corrigan, C. J., Br. Med. Bull., 1992, 48, 51-64].
  • Chemokines are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils [Luster, New Eng. J. Med., 1998, 338, 436-45; Rollins, Blood, 1997, 90, 909-28]. To date, almost 40 human chemokines have been well characterised [Schwarz, M. K., ibid; Wells, T. N. C. et: al., Trends Pharmacol.
  • CXC cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC).
  • CXC cysteines in the amino acid sequence are separated by a single amino acid
  • CC CX3C chemokine
  • CXC chemokines lymphotactin-1 and lymphotactin-2
  • fractalkine CX3C chemokine
  • CXC chemokines such as interleukin-8 (IL-8), neutrophil- activating protein-2 (NAP-2) and melanoma growth stimulatory activating protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes
  • CC chemokines such as RANTES (regulation-upon-activation, normal T-cell expressed and secreted)
  • MIP-1 ⁇ , MIP-1 ⁇ , the monocyte chemotactic proteins MCP-1 , MCP-2, MCP-3, MCP-4, MCP-5) and ⁇ the eotaxins (-1 , -2 and -3) are chemotactic for macrophages, T lymphocytes, eosinophils, dendritic cells and basophils.
  • the chemokines bind to specific cell-surface receptors. Seventeen mammalian receptors have been reported to date [Schwarz, M. K., ibid], all of which are seven-transmembrane-spanning G-protein coupled receptors. The ligand-binding characteristics of these receptors have been identified; for example, the ligands for CCR-1 are RANTES, MIP-1 ⁇ and MCP-3, whilst those for CCR-2 are MCP-1 , 2, 3, 4 and 5. Chemokines and their receptors have been implicated as important mediators of inflammatory, infectious and immunoregulatory diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • the CXCR3 chemokine receptor is expressed primarily in T lymphocytes, and its functional activity can be measured by cytocolic calcium elevation or chemotaxis.
  • the receptor was previously referred to as GPR9 or CKR-L2. Its chromosomal location is unusual among the chemokine receptors in being localised to Xq13.
  • Ligands that have been identified that are selective and are of high affinity are the CXC chemokines, interferon- gamma inducible protein (IP10), monokine induced by interferon-gamma (MIG) and interferon-inducible T-cell alpha chemoattractant (ITAC).
  • CXCR3 The highly selective expression of CXCR3 makes it an ideal target for the intervention to interrupt inappropriate T-cell trafficking.
  • the clinical indications for such intervention are in T-cell mediated diseases such as multiple sclerosis, rheumatoid arthritis and type I diabetes. Inappropriate T- cell infiltration also occurs in psoriasis and other pathogenic skin inflammation conditions, although the diseases may not be true autoimmune disorders.
  • up-regulation of IP-10 expression in keratinocytes is a common feature in cutaneous immunopathologies. Inhibition of CXCR3 can be beneficial in reducing rejection in organ transplantation.
  • R when present, is an atom or group -L 2 (Alk 2 ) m L 3 (R 5 ) n in which L 2 and L 3 , which may be the same or different, is each a covalent bond or a linker atom or group; m is zero or the integer 1 ; n is the integer 1 , 2 or 3; Alk 2 is an optionally substituted aliphatic or heteroaliphatic chain; and R 5 is a hydrogen or halogen atom or a group selected from alkyl, -OR 6 [where R 6 is a hydrogen atom or an optionally substituted alkyl group], -SR 6 , -NR 6 R 7 [where R 7 is as just defined for R 6 and may be the same or different], -NO 2 , -CN, -CO2R 6 , -OCO2R 6 , -CONR 6 R 7 , -OCONR 6 R 7 , -CSNR
  • a indicates the point of attachment of any available ring carbon in the ring Cy to the group L 1 ; b indicates the point of attachment to Alk 1 ; s and t, which may be the same or different, is each zero or the integer 1 or 2, provided that s + t is the integer 1 , 2, 3 or 4; R 4 is ' an optionally substituted alkyl group; and W is a pharmaceutically acceptable counterion; Alk 1 is a covalent bond or an optionally substituted straight or branched
  • Ci- 6 alkylene chain; and E is an optionally substituted C 7tician ⁇ 0 cycloalkyl, C -10 cycloalkenyl or C . 10 polycycloaliphatic group; and the salts, solvates, hydrates, tautomers or ⁇ /-oxides thereof.
  • certain compounds of formula (1 ) may exist as geometric isomers (E or Z isomers).
  • the compounds may also have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • Formula (1 ) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.
  • the compounds of the invention may be administered in a pharmaceutically acceptable pro-drug form, for example as a protected carboxylic acid derivative, e.g. as a physiologically acceptable ester.
  • pro- drugs may be converted in vivo to the active compounds of formula (1 ), and the invention is intended to extend to such pro-drugs.
  • pro-drugs are well known in the literature; see, for example, International Patent Application No. WO 00/23419; Bodor, N. (Alfred Benzon Symposium, 1982, 17, 156-177); Singh, G. et al. (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard, H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).
  • alkyl whether present as a group or part of a group, includes optionally substituted straight or branched C ⁇ _ 0 alkyl groups, for example Chalky! groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl or neo-pentyl groups.
  • Optional substituents when present on these groups include those optional substituents mentioned hereinafter.
  • aliphatic chain is intended to include optionally substituted straight or branched C 2 - ⁇ oalkenylene, e.g. C 2 - 6 al enylene, or C 2 - ⁇ oalkynylene, e.g. C 2 -6alkynylene, groups.
  • aliphatic chains include optionally substituted straight or branched C ⁇ - 6 alkylene chains such as -CH 2 -, -CH2CH2-, -CH(CH 3 )CH2-, -(CH 2 )2CH 2 -, -(CH 2 ) 3 CH2-, -CH(CH3)(CH 2 )2CH2-, -CH 2 CH(CH 3 )CH2-, -C(CH 3 ) 2 -, -C(CH 3 )2CH 2 -, -CH 2 C(CH 3 )2CH2-, -(CH 2 )2CH(CH 3 )CH2-, -CH(CH 3 )CH 2 CH2-, -CH(CH 3 )CH 2 CH(CH3)CH2-, -CH 2 CH(CH3)CH 2 CH2-, -(CH 2 )2C(CH 3 )2CH2-, -(CH 2 ) 4 CH 2 - or -(CH 2 ) 5 CH 2 ; C ⁇ alkenylene chains such as
  • More particular examples include optionally substituted C- ⁇ - 3 aIkylene chains selected from -CH 2 -, -CH 2 CH 2 -, -CH 2 CH2CH2-, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 - and -CH 2 CH(CH 3 )- chains.
  • heteroaliphatic chain is intended to include the optionally substituted aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 4 where L 4 is a linker atom or group.
  • Each L 4 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
  • L 4 When L 4 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms and -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -N(R 14 )- [where R 14 is a hydrogen atom or a Chalky!
  • cycloaliphatic group includes optionally substituted non-aromatic cyclic or multicyclic, saturated or partially saturated C 3 - ⁇ 0 ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbornyl, norbornenyl, bicyclo[2.2.1]heptanyl or bicyclo[2.2.1]heptenyl.
  • heterocycloaliphatic group refers to an optionally substituted non-aromatic 3- to 10-membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system containing one, two, three or four heteroatoms or heteroatom-containing groups L 4 as defined above.
  • heterocycloaliphatic groups include those substituents mentioned hereinafter.
  • heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e.g. 1 ,3- dioxolanyl, imidazolinyl, e.g.
  • 2-imidazolinyl imidazolidinyl, pyrazolinyl, e.g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e.g.
  • the optional substituents which may be present on the alkyl, cycloaliphatic or heterocycloaliphatic groups described above include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH 2 ), substituted amino, optionally substituted C 6 . 12 arylamino, -CN, -CO 2 H, -CO 2 R 9 (where R 9 is an optionally substituted
  • R 11 and R 12 which may be the same or different, is each a hydrogen atom or a Ci-ealkyl group
  • R 11 and R 12 which may be the same or different, is each a hydrogen atom or a Ci-ealkyl group
  • alkyI group optionally substituted by one, two, three or more of the same or different atoms or groups selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy, thiol, alkylthio, amino, substituted amino, optionally substituted
  • Substituted amino groups include -NHR 10 and -N(R 10 )(R 11 ) groups.
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains, for example Alk 2 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g.
  • R 11b is an optionally substituted d ⁇ alkyl group
  • R 11b is an optionally substituted d ⁇ alkyl group
  • -CO 2 CH 3 or -CO 2 C(CH 3 ) 3 e.g. -CONHR 11b , e.g. -CONHCH 3 , -CON(R 11b ) 2 , e.g. -CON(CH 3 ) 2 , -COR 11b , e.g. -COCH 3 , C.,. 6 alkoxy, e.g. methoxy or ethoxy, haloC ⁇ . 6 alkoxy, e.g.
  • the optional substituents which may be present on alkylene chains, for example Alk 1 include those as just defined for aliphatic or heteroaliphatic chains.
  • Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom.
  • Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1 ) by any available ring carbon or, where available, ring nitrogen atom.
  • the cycloalkyl and cycloalkenyl groups represented by E include non-aromatic cyclic or multicyclic, saturated or partially saturated C 7 . ⁇ 0 cycloalkyl or C 7 _ ⁇ ocycloalkenyl ring systems.
  • the cycloalkyl and cycloalkenyl groups may be substituted with one or more substituents as described hereinafter.
  • the C - ⁇ opolycycloaliphatic groups represented by E include optionally substituted C 7 . 10 bi- or tricycloalkyl or C 7 _ ⁇ 0 bi- or tricycloalkenyl groups.
  • Examples of groups represented by E include, but are not limited to, optionally substituted cyclooctyl, cyclononyl, cyclodecyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, adamantanonyl, noradamantyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.1]octenyl, bicyclo[3.3.1]nonanyI, bicyclo[6.2.0]decanyl, octahydro-4,7-methanoindenyl or octahydronaphthalenyl.
  • Optional substituents which may be present on the group E include one, two, three or more substituents, which each may be the same or different, selected from oxo, alkoxy, haloalkyl, e.g. -CF 3 or -CF 2 H, haloalkoxy, e.g. -OCF 2 H, hydroxy (-OH), thiol (-SH), alkylthio, -CN, -CO 2 H, -CO 2 R 9a (where R 9a is an optionally substituted d-ealkyl group), -SO 3 H, -SOR 10a (where R 10a is a C h alky!
  • R 11a and R 12a which may be the same or different, is each a hydrogen atom or a C h alky! group
  • R 11a and R 12a which may be the same or different, is each a hydrogen atom or a C h alky! group
  • alkyl or C 2 - 6 alkenyl group optionally substituted by one, two, three or more of the same or different halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH 2 ), substituted amino, optionally substituted C 6 .
  • halogen atom is intended to include fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F and -CH 2 CI groups.
  • alkoxy as used herein is intended to include straight or branched C ⁇ _ 10 alkoxy, for example C ⁇ _ 6 alkoxy such as methoxy, ethoxy, n- propoxy, isopropoxy and ferf-butoxy.
  • Haloalkoxy as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include -OCF 3 , -OCCI 3 , -OCHF 2 , -OCHCI 2 , -OCH 2 F and -OCH 2 CI groups.
  • alkylthio is intended to include straight or branched C ⁇ - ⁇ 0 alkylthio, e.g. C-i. s alkylthio such as methylthio or ethylthio groups.
  • aromatic group and "aryl group” are intended to include for example optionally substituted monocyclic ring C 6 _ 12 aromatic groups, such as phenyl, or bicyclic fused ring C 6 _ 12 aromatic groups, such as 1- or 2-naphthyl groups.
  • heteroaryl group and “heteroaryl group” are intended to include for example optionally substituted Ci.gheteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof).
  • the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms. Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R 16 atoms or groups as defined below.
  • monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, ⁇ /-C ⁇ _ 6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl.
  • bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo[1 ,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-Ju]pyridyI, pyrido[3,2-/->]pyridyl, pyrido[4,3-/?]pyridyl, quinolinyl, isoquinolinyl and phthalazinyl.
  • Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R 16 in which R 16 is -R 16a or -Alk 4 (R 16a ) f , where R 16a is a halogen atom, or an amino (-NH 2 ), -NHR 17 [where R 17 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl or heteroaryl group, or -Alk 4 (R 17a ) f , where R 17a is the same as R 17 ], -N(R 17 ) , nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-CO 2 H), -CO 2 R 17 , thiol (-SH), -SR 17 , -OR 17 , -COR I7 , -CSR 7 , -SO 3 H, -SOR 17 , -SO
  • R 16a or R 17a When in the group -Alk (R 16a ) f or -Alk 4 (R 17a ) f f is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R 16a or R 17a may be present on any suitable carbon atom in -Alk 4 . Where more than one R 16a or R 17a substituent is present these may be the same or different and may be present on the same or different atom in -Alk 4 . Clearly, when f is zero and no substituent R 16a or R 7a is present the alkylene, alkenylene or alkynylene chain represented by -Alk 4 becomes an alkyl, alkenyl or alkynyl group.
  • each may be for example an optionally substituted 2- or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group.
  • -Het 2 may represent, for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those substituents described above in relation to aromatic groups.
  • Particularly useful atoms or groups represented by R 16 include fluorine, chlorine, bromine, iodine, C ⁇ . 6 alkyl, haloC ⁇ ealkyl, e.g. -CF 3 , haloC ⁇ _ 6 alkoxy, e.g.
  • R 17 groups include -Alk 4 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic, -Alk 4 phenyl, -Alk 4 monocyclic heteroaryl, -Alk 4 monocyclic heterocycloaliphatic, and -Alk 4 cycloaliphatic.
  • R 18 is particularly hydrogen or methyl.
  • -Alk 4 When -Alk 4 is present it may be for example a methylene, ethylene, n- propylene, isopropylene, ⁇ -butylene, isobutylene, sec-butylene, terf-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2- propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S- atoms or -S(O)-, -S(O) 2 - or -N(R 18 )- groups.
  • Ci- ⁇ alkylene chains especially C ⁇ - 3 alkylene chains, e.g. methylene, ethylene or propylene, or, when f is zero, C ⁇ - 6 alkyl groups, especially C ⁇ _ alkyl groups, e.g. methyl, ethyl, r/-propyl, isopropyl, n-butyl or te/f-butyl.
  • aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may be represented by -R 16a , -R 17 or -R 17a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, ⁇ /-C ⁇ .
  • Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by -R 16a , -R 17 or -R 17a include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl, -OCH 3 , -OCF 3) -OCF 2 H, -CF 3 , -CN, -NHCH 3 , -N(CH 3 ) 2 , -CONH 2 , -CONHCH3, -CON(CH 3 ) 2 , -CO2CH3, -CO 2 CH 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH 3 , -NHCOCH 3) -N(CH 3 )COCH 3l -SCH 3 , -SO2CH3 or -CO 2 H.
  • Optional substituents which may in particular be present on the heterocycloaliphatic or cycloaliphatic groups represented by -R 16a , -R 17 or -R 17a include one, two, three or more atoms or groups selected from -OCH 3 , -OCF 3 , -OCF 2 H, -CF 3 , d-salkylthio, straight or branched d-salkyl, -CN, -NHCH 3 , -N(CH 3 ) 2 , -CONH2, -CONHCH3, -CON(CH 3 ) 2 , -CO 2 CH 3> -CO2CH2CH3, -CO 2 C(CH 3 )3, -COCH3, -NHCOCH 3l -N(CH 3 )COCH 3 or -CO 2 H.
  • two adjacent R 16 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C ⁇ _ 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy, or a C 3 _ 6 cycloalkyl or 3- to 10-membered monocylic heterocycloaliphatic group as defined herein.
  • a cyclic ether e.g. a C ⁇ _ 6 alkylenedioxy group such as methylenedioxy or ethylenedioxy
  • C 3 _ 6 cycloalkyl or 3- to 10-membered monocylic heterocycloaliphatic group as defined herein.
  • Optional substituents which may be present on any available carbon of the ring Cy include one, two or three substituents, R A , where R A is a halogen atom or an alkyl group.
  • R A is a halogen atom or an alkyl group.
  • Cy may be substituted by a halogen atom or a straight or branched C ⁇ - ⁇ 0 alkyl group as defined herein.
  • heterocycloaliphatic rings represented by Cy in compounds of the invention include: where s is the integer 1 , t is zero or the integer 1 or 2 (especially the integer 1 ), and a, b, W and R 4 are as described earlier, or
  • Linker atoms or groups L 2 and L 3 when present in the group R, R 1 or R 2 in compounds of the invention, may be any of the linker atoms or groups as previously defined for L 4 . Each linker atom or group may be the same or different. When the groups R 6 and R 7 or R 7 and R 8 are both present in the group R, R 1 or R 2 as alkyl groups these groups may be joined together with the N atom to which they are attached to form a heterocyclic ring.
  • heterocyclic rings may be optionally interrupted by a further heteroatom selected from -O-, -S- or -N(R 6 )-.
  • Particular examples of such heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.
  • Examples of the substituents represented by R, R 1 or R 2 when present in compounds of the invention include atoms or groups -L 2 Alk 2 L 3 R 5 , -L 2 Alk 2 R 5 , -L 2 R 5 , -R 5 , -Alk 2 R 5 and -Alk 2 (R 5 ) n , wherein L 2 , Alk 2 , L 3 , R 5 and n are as defined above.
  • substituents include -L 2 CH 2 L 3 R 5 , -L 2 CH(CH 3 )L 3 R 5 , -L 2 (CH 2 ) 2 L 3 R 5 , -L 2 CH 2 R 5 , -L 2 CH(CH 3 )R 5 , -L 2 (CH 2 ) R 5 , -CH 2 R 5 , -CH(CH 3 )R 5 , -(CH 2 ) 2 R 5 and -R 5 groups.
  • Particularly useful atoms or groups represented by R, R 1 or (where relevant) R 2 in compounds of the invention include, for example, halogen atoms, e.g.
  • fluorine, chlorine, bromine or iodine atoms, and C ⁇ - 6 alkyl e.g. methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl or ferf-butyl, optionally substituted d-scycloalkyl, e.g. optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted d-rheterocycloalkyl, e.g.
  • pyrrolidinyl piperidinyl, imidazolidinyl, morpholinyl or piperazinyl
  • C ⁇ - 6 hydroxyalkyl e.g. hydroxymethyl, hydroxyethyl or -C(OH)(CF 3 ) 2
  • carboxyC ⁇ -6alkyl e.g. carboxyethyl, C ⁇ . 6 alkylthio e.g. methylthio or ethylthio, carboxyC ⁇ - 6 alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio
  • Ci- ⁇ alkoxy e.g.
  • C ⁇ _ 6 alkylaminoC ⁇ - 6 alkyl e.g. ethylaminoethyl, C ⁇ - 6 dialkylamino- Ci- ⁇ alkyl, e.g. diethylaminoethyl, aminoCi-ealkoxy, e.g. aminoethoxy, C ⁇ - 6 alkyIaminoC ⁇ - 6 alkoxy, e.g. methylaminoethoxy, C ⁇ - 6 dialkylaminoC ⁇ - 6 alkoxy, e.g.
  • Alk 5 [where Alk 5 is an optionally substituted alkyl group] C 1 - 6 alkanoyl e.g. acetyl, thiol (-SH), thioC ⁇ _ 6 alkyl, e.g.
  • thiomethyl or thioethyl sulphonyl (-SOsH), -SOsAlk 5 , Ci- ⁇ alkylsulphinyl, Ci- ⁇ alkylsulphonyl, e.g methylsulphonyl, aminosulphonyl (-SO 2 NH 2 ), C ⁇ _ 6 alkylaminosulphonyl, e.g methylaminosulphonyl or ethylaminosulphonyl, C ⁇ _ 6 dialkylaminosulphonyl, e.g dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl carboxamido (-CONH 2 ), C ⁇ .
  • alkylaminocarbonyl e.g. methylaminocarbonyl or ethylaminocarbonyl
  • C ⁇ - 6 diaIkylaminocarbonyl e.g. dimethylaminocarbonyl or diethylaminocarbonyl
  • aminoCi- ⁇ alkylaminocarbonyl e.g. aminoethyl- aminocarbonyl
  • C ⁇ - 6 dialkylaminoC ⁇ - 6 alkylaminocarbonyl e.g. diethylaminoethyl- aminocarbonyl, aminocarbonylamino
  • Ci- ⁇ alkylaminocarbonylamino e.g.
  • Ci- ⁇ dialkylamino- carbonylamino e.g. dimethylaminocarbonylamino or diethylaminocarbonyl- amino, C ⁇ . 6 alkylaminocabonylC ⁇ . 6 alkylamino, e.g. methylaminocarbonyl- methylamino, aminothiocarbonylamino, Ci- ⁇ alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C ⁇ _ 6 dialkyl- aminothiocarbonylamino, e.g.
  • aminoacetylamino C ⁇ - 6 dialkylaminoC ⁇ -6alkanoyl- amino, e.g. dimethylaminoacetylamino, C ⁇ - 6 alkanoylaminoC ⁇ . 6 alkyl, e.g. acetyl- aminomethyl, d-ealkanoylaminod-ealkylamino, e.g. acetamidoethylamino, C ⁇ - 6 alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or ferf-butoxycarbonylamino, optionally substituted C 6 - ⁇ 2 aryl, e.g.
  • R substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a Ci- ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy.
  • R substituents when two R substituents are on adjacent carbon atoms of the heteroaromatic ring of formula (1 ) they may be joined to form, together with the heteroaromatic ring carbon atoms to which they are joined, a heteroaromatic ring-fused optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic ring where such rings and optional substituents are as previously defined. It will be appreciated that where two or more R substituents are present these need not necessarily be the same atoms and/or groups. In general the substituent(s) may be present on any available ring position in the heteroaromatic ring in compounds of formula (1 ).
  • R 10 , R 10a , R 11 , R 11a , R 11b , R 12 , R 12a , R 13 , R 13a , R 14 or R 18 is present as a Ci-ealkyl group it may be a straight or branched d_ 6 alkyl group, e.g. a C ⁇ _ 3 alkyl group such as methyl, ethyl or isopropyl.
  • d_ 6 alkyl group e.g. a C ⁇ _ 3 alkyl group such as methyl, ethyl or isopropyl.
  • optionally substituted alkyl groups present in ester groups of formulae -CO 2 R 9 , -CO 2 R 9a , -CO 2 R 11b and -CO 2 Alk 5 include d- ⁇ alkyl groups as herein described.
  • Optional substituents which may be present on these alkyl groups, include optionally substituted cycloaliphatic, aromatic or heteroaromatic groups as herein defined.
  • R 4 when present in compounds of formula (1 ) as an optionally substituted alkyl group may be any optionally substituted alkyl group as previously defined.
  • Particular examples of such groups include Ci-ealkyl groups and optionally substituted C 6 - ⁇ 2 arylC ⁇ _ 6 alkyl groups, especially methyl, ethyl and optionally substituted benzyl groups.
  • a pharmaceutically acceptable counterion means an ion having a charge opposite to that of the substance with which it is associated and that is pharmaceutically acceptable.
  • Representative examples include, but are not limited to, chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, nitrate, sulfate, phosphate, carbonate, propionate, malonate and the like, such as are described in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA, 1985.
  • the presence of certain substituents in the compounds of formula (1 ) may enable salts of the compounds to be formed.
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p- toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogensulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • r is the integer 1.
  • X is a N atom.
  • X is a C(R 1 ) group.
  • Y is a N atom.
  • Y is a C(R 1 ) group.
  • Z is a N atom.
  • Z is a C(R 1 ) group.
  • R 1 is hydrogen.
  • X and Z is each a N atom and Y is a group C(R 1 ).
  • R 1 is a hydrogen atom.
  • X is a N atom, and Y and Z are both C(R 1 ).
  • R 1 is a hydrogen atom.
  • One particular group of compounds of the invention has the formula
  • R, q, X, Z, L 1 , Cy, Alk 1 and E are as defined for formula (1 ).
  • q is preferably zero or the integer 1 or 2.
  • Suitable values of R include halogen, Ci-ealkyl, trifluoromethyl, C ⁇ _ 6 alkoxy, trifluoromethoxy, nitro and optionally substituted phenyl. Examples of typical substituents on R include halogen, trifluoromethyl, C ⁇ _ 6 alkoxy and cyano.
  • R Detailed values of R include fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro, chlorophenyl, dichlorophenyl, trifluoromethyl-phenyl, methoxyphenyl and cyanophenyl.
  • Representative values of R include halogen, C ⁇ _ 6 alkyl, trifluoromethyl, Ci- ⁇ alkoxy, trifluoromethoxy and nitro.
  • Specific values of R include fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy and nitro.
  • R or R 1 substituents when present in compounds of formula (1 ) or (2) include halogen atoms, especially fluorine, chlorine or bromine atoms, or C ⁇ - 3 alkyl, especially methyl, halomethyl, especially -CF 3 or -CHF 2 , methoxy, halomethoxy, especially -OCF 3 or -OCHF 2> -CN, -CO 2 R 6 , especially -CO 2 CH 3> -COR 6 , especially -COCH 3 , -NO 2 , amino (-NH 2 ), substituted amino (-NR 6 R 7 ), especially -NHCH3 or -N(CH 3 ) 2 , and -N(R 6 )COR 7 , especially -NHCOCH 3 , groups.
  • halogen atoms especially fluorine, chlorine or bromine atoms, or C ⁇ - 3 alkyl, especially methyl, halomethyl, especially -CF 3 or -CHF 2 , methoxy, halome
  • X in one particular group of compounds of formula (2) is a N atom or a C(H) group. In compounds of this class X is most preferably a N atom.
  • Z is in particular an O or S atom or a N(R 2 ) group, where R 2 is a hydrogen atom or an optionally substituted C ⁇ _ 6 alkyl group.
  • Especially useful NR 2 groups include NH, NCH 3 and NCH 2 Ph where Ph is an optionally substituted phenyl ring, most especially NH or NCH 3 .
  • Z is O.
  • Z is S.
  • Z is NH.
  • L 1 is absent. In another embodiment of the compounds according to the invention, L 1 represents N(R 3 ). In a specific embodiment, L 1 is NH.
  • R 3 suitably represents hydrogen, C ⁇ _ 6 alkyl, C 3 _ 7 cycloalkylC ⁇ - 6 alkyl or C ⁇ - 6 alkoxyC ⁇ - 6 alkyl. Particular values of R 3 include hydrogen, methyl, cyclopropylmethyl and methoxypropyl. A specific value of R 3 is hydrogen.
  • L 1 in compounds of formula (1 ) or (2) is preferably an O atom or a N(R 3 ) group.
  • R 3 is in particular a hydrogen atom or an optionally substituted C 1 - 6 alkyl, especially C 1 - 3 alkyl, group.
  • Especially useful NR 3 groups include NH, NCH 3 and NCH 2 Ph where Ph is an optionally substituted phenyl ring.
  • L 1 is an O atom or an NH or NCH 3 group.
  • Cy in compounds of formula (1 ) or (2) is most especially:
  • R 4 in one particular group of compounds of the invention is a C ⁇ _ 3 alkyl group, such as a methyl or ethyl group, especially a methyl group.
  • Alk 1 in one group of compounds of formula (1) or (2) is preferably a C ⁇ _ 3 alkylene chain, in particular -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -, more particularly -CH 2 -.
  • Alk 1 in another group of compounds of formula (1 ) or (2) is a covalent bond.
  • One group of compounds has the formula (1 ) or (2) wherein E is selected from optionally substituted cycloheptyl, cyclooctyl, cyclononyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptenyl, bicyclo[3.1.1]heptanyl or bicyclo[3.1.1]heptenyl.
  • Particular substituents which may be present on the group E, are one, two, three or more groups selected from hydroxy, optionally substituted phenyl or monocyclic heteroaromatic, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 H, or optionally substituted straight or branched d. 6 alkyl or C 2 _ 6 alkenyl, wherein the optional alkyl or alkenyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group.
  • Particular examples of the optionally substituted Ci-ealkyl or C 2 Particular examples of the optionally substituted Ci-ealkyl or C 2 .
  • 6 alkenyl groups are -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 3 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 3> -C(CH 3 ) 3 .
  • E is substituted with one, two, three or more methyl groups.
  • E in one particular group of compounds of the invention is a 1- cyclooctenyl, 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl, adamantyl or cyclooctyl group.
  • E is especially a 6,6- dimethylbicyclo[3.1.1]hept-2-en-2-yl group.
  • optional substituents which may be present on cycloaliphatic or heterocycloaliphatic groups in compounds of formula (1) or
  • (2), in particular on the E group substituents, are one, two or three groups selected from C 1 - 3 alkoxy, -OCF 3 , -OCF 2 H, -CF 3 , C ⁇ alkylthio, -CN, -NHCH 3 ,
  • aromatic or heteroaromatic substituents which may be present on compounds of formula (1 ), in particular on the E group substituents, are one, two or three atoms or groups selected from fluorine, chlorine, bromine, straight or branched C ⁇ - 3 alkyl, methoxy, -OCF 3 , -OCF 2 H, -CF 3 , -CN, -NO2, -NH 2 , -NHCH3, -N(CH 3 ) 2 , -CONH 2 , -CONHCH3, -CON(CH 3 ) 2 , -CO 2 CH 3 , -CO 2 CH 2 CH 3 or -CO 2 H.
  • Compounds according to the invention are potent and selective inhibitors of chemokines binding to the CXCR3 receptor as demonstrated by differential inhibition of this receptor when compared to other chemokine receptors, such as CCR3.
  • the ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
  • the compounds are of use in modulating chemokine-mediated cell signalling and in particular are of use in the prophylaxis and/or treatment of diseases or disorders involving inappropriate T-cell trafficking.
  • the invention extends to such a use and to the use of the compounds of formula (1 ) or (2) for the manufacture of a medicament for treating such diseases and disorders.
  • Particular diseases include inflammatory, autoimmune and immunoregulatory disorders.
  • inflammatory or allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis; spondyloarthropathies; scleroderma; respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases and the like; (2) autoimmune diseases, such as arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, diabetes, glomerulonephritis and the like; (3) graft rejection (including allograft rejection and graft-v-host disease); and (4) other diseases
  • the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example for the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, allograft rejection and graft-v-host disease.
  • the compounds of formula (1 ) or (2) can be used alone or in combination with other compounds having related utilities to prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as multiple sclerosis, rheumatoid arthritis and atherosclerosis, and those pathologies as discussed herein.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1 ) or (2) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions of this invention comprise a compound of formula (1) or (2) or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant or an anti-inflammatory agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • compositions may also contain buffer salts, and flavouring, colouring or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound
  • buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (1) or (2) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen- free water, before use.
  • a suitable vehicle e.g. sterile pyrogen- free water
  • the compounds of formula (1 ) or (2) may be coated on particles such as microscopic gold particles.
  • the compounds of formula (1 ) or (2) may also be formulated as a depot preparation. Such long- acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • the compounds of formula (1 ) or (2) may be formulated as a suppository. These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature. Such materials include, for example, cocoa butter and polyethylene glycols.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and around 0.05 mg to around 1000 mg, e.g.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.
  • the symbols R, X, Y, Z, q, s, t, L 1 , Cy, Alk 1 , E, R 4 and W when used in the formulae depicted, are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated.
  • a compound of formula (1 ) may be prepared by reaction of an amine or alcohol of formula (ii), wherein L 1 is an O atom or a N(R 3 ) group, with a compound of formula (i), wherein V is a leaving group.
  • suitable leaving groups include halogen atoms, e.g. fluorine, bromine, iodine or chlorine atoms, alkylsulfonyl groups, e.g. methanesulfonyl, or sulfonyloxy groups such as alkylsulfonyloxy, e.g.
  • bases may include, but are not limited to, silazanes, e.g. lithium hexamethyldisilazane (LiHMDS) or sodium hexamethyldisilazane (NaHMDS), carbonates, e.g. potassium carbonate, hydrides, e.g. sodium hydride, or organic amines, e.g.
  • reaction may be performed in an organic solvent such as an amide, e.g. a substituted amide such as ⁇ /,/V-dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or 1 ,4-dioxane, or /V-methylpyrrolidone or acetonitrile, at a temperature from ambient to the reflux temperature.
  • an organic solvent such as an amide, e.g. a substituted amide such as ⁇ /,/V-dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or 1 ,4-dioxane, or /V-methylpyrrolidone or acetonitrile, at a temperature from ambient to the reflux temperature.
  • the reaction may be performed at an elevated temperature in the presence of microwave irradiation.
  • an amine of general formula (iii) where P is a suitable protecting group, e.g. terf-butoxycarbonyl may be reacted with a compound of formula E-Alk 1 -T (v), wherein T is a suitable leaving group (e.g. a halogen atom, such as chlorine or bromine, or an arylsulfonyloxy group, such as p-toluene- sulfonyloxy), to give a compound of general formula (vi).
  • the reaction may be performed in the presence of a base such as potassium carbonate in, for example, refluxing acetonitrile or ⁇ /, ⁇ /-dimethylformamide at around ambient temperature.
  • the protected amine of general formula (vi) may be prepared by reductive alkylation of a compound of formula (iii) with a compound of formula E-Alk 1b (iv), wherein Alk 1b is a suitable precursor to Alk 1 , for example Alk 1b contains a reactive group such as a reactive carbonyl.
  • This reaction may be achieved using methods known to those skilled in the art.
  • Alk 1b is an aldehyde
  • appropriate conditions may include the use of a suitable borohydride as reductant, for example sodium triacetoxy- borohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g.
  • the compounds of formula (v) may be prepared from an alcohol of general formula E-AIk 1 -OH (vii) using standard methodology known to those skilled in the art.
  • T is an arylsulfonate ester, e.g.
  • p- toluenesulfonyloxy this may be prepared by reaction of the alcohol (vii) with p-toluenesulfonyl chloride in the presence of an amine base, e.g. triethylamine, in an appropriate solvent, such as dichloromethane or tetrahydrofuran.
  • the compounds of formula (vii) may also be used to prepare the compounds of formula (iv) using standard oxidising conditions such as those described herein.
  • the intermediate compound of formula (vi) may be deprotected using standard methodology, for example by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, to give an amine starting material of general formula (ii). It will be appreciated by those skilled in the art that alcohols of formula
  • ( ⁇ ) may also be prepared in a similar manner.
  • the use of protecting groups may not be required, particularly when reductive alkylation is employed.
  • the order of reactions in which a compound of formula (1 ) or (2) is prepared may be varied.
  • a compound of formula (viii): (Viii) where L 1 is an O or N(R 3 ) group, and P is as defined above; may be reacted with compound of general formula (i) using the reactions just described to yield a compound of formula (ix): (ix)
  • the resulting compound of formula (ix) may be deprotected using methods known to those skilled in the art and reacted with a compound of general formula (iv) or (v) using standard techniques, such as the methods described herein.
  • Compounds of formula (1) or (2), in which L 1 is absent may be prepared as shown in Scheme (C) below:
  • a compound of formula (i) may be reacted with an organometallic reagent such as butyllithium in an organic solvent such as diethyl ether or tetrahydrofuran at -78°C, followed by addition of a ketone of formula (x).
  • the resulting intermediate may then be treated with acid, e.g. trifluoroacetic acid, in a halogenated hydrocarbon, e.g. dichloromethane, to give a compound of formula (xi).
  • Compounds of formula (1) or (2) may be prepared by reduction of a compound of formula (xi) using methods known to those skilled in the art, e.g. hydrogenation in the presence of a palladium catalyst. It will be appreciated by the person skilled in the art that a compound of formula (xii), wherein P is a protecting group, may be used as an alternative to compounds of formula (x):
  • the protecting group may be removed using standard methodology at the end of the procedure described in Scheme (C) and the resulting amine manipulated using methods as described above to give a compound of formula (1) or (2).
  • the compounds of formula (2) wherein X is N, Z is NH and L 1 is absent may be prepared by a process which comprises cyclising a compound of formula (xiii):
  • a bromide or chloride of formula (i) may be prepared by treatment of a compound of formula (xiv) with an alkyl nitrite, for example fe/f-butyl nitrite, or sodium nitrite in the presence of an acid, e.g. sulphuric acid or hydrochloric acid, followed by addition of a copper salt, for example copper(l) or copper(ll) bromide or chloride, in the presence of a solvent, for example a nitrile such as acetonitrile or acetic acid, at a temperature from about 0°C to around 65°C.
  • the intermediates of formula (xiii) may be prepared by reacting a compound of formula Q 1 -Cy-Alk 1 -E with a compound of formula (xv):
  • Q 1 represents an activated carboxylate moiety, e.g. an acid chloride functionality -COCI.
  • the reaction is conveniently carried out in the presence of a base, e.g. diisopropyl- ethylamine, in a solvent such as dichloromethane.
  • a base e.g. diisopropyl- ethylamine
  • the intermediates of formula Q 1 -Cy-Alk 1 -E wherein Q 1 is -COCI may suitably be prepared from the corresponding compound wherein Q 1 is a carboxylic acid moiety -CO 2 H by treatment with oxalyl chloride.
  • the latter compound may in turn be prepared from a precursor ester derivative, e.g.
  • compounds of formula (1) or (2), or any preceding intermediates may be further derivatised by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formula (1 ), where appropriate functional groups exist in these compounds.
  • compounds of formula (1 ) or (2) which contain the group R 4 may be prepared from a compound of formula (1 ) or (2) using the general method as shown in Scheme D:
  • a compound of formula (1) may be reacted with an alkylating agent R 4 -W such as an alkyl halide, e.g. methyl or ethyl iodide, or a benzyl halide such as benzyl bromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. methanol or ethanol, an ether, e.g. diethyl ether, or a mixture of such solvents, at, for example, ambient temperature.
  • an alkylating agent R 4 -W such as an alkyl halide, e.g. methyl or ethyl iodide, or a benzyl halide such as benzyl bromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, an alcohol, e.g. methanol or ethanol, an ether, e.
  • ester groups may be converted to the corresponding acid [-CO 2 H] by acid- or base-catalysed hydrolysis depending on the nature of the ester.
  • Acid- or base-catalysed hydrolysis may be achieved, for example, by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid, in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as 1 ,4-dioxane or an alkali metal hydroxide, e.g. lithium hydroxide, in an aqueous alcohol, e.g. aqueous methanol.
  • an acid [-CO 2 H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.
  • -OH groups may be generated from a corresponding ester or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid [-CO 2 H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy, or arylsulfonyloxy, e.g. p-toluenesulfonyloxy, group, using conditions known to the skilled artisan.
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon, e.g., dichloromethane, to yield the corresponding chloride.
  • a base e.g. triethylamine, may also be used in the reaction.
  • Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well-known conditions.
  • an oxidising agent such as a periodinane, e.g. Dess Martin
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane.
  • An alternative oxidation procedure may be suitably brought about by activating dimethylsulfoxide using, for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine.
  • Suitable conditions for this reaction may be using an appropriate solvent, for example a halogenated hydrocarbon, e.g.
  • ⁇ , ⁇ -Unsaturated aldehydes for example, of formula OHC-E, where E is cycloalkenyl
  • ⁇ , ⁇ -Unsaturated aldehydes may be prepared by hydrolysis of a corresponding allylic nitro compound. This may be achieved, for example, by treatment of the allylic nitro compound with a base, such as sodium methoxide or potassium te/f-butoxide, followed by addition of a buffered aqueous titanium trichloride solution.
  • the allylic nitro compound may be prepared by nucleophilic addition of nitromethane to the corresponding ketone, followed by elimination of water.
  • Suitable conditions for this reaction may be refluxing in toluene under Dean-Stark conditions, in the presence of an amine base, such as ⁇ /, ⁇ /-dimethylethylene diamine.
  • an amine base such as ⁇ /, ⁇ /-dimethylethylene diamine.
  • these aldehydes may be used in reductive alkylations to give compounds of formula (1) where Alk 1 is -CH 2 - using the conditions described herein.
  • primary amine [-NH 2 ] or secondary amine [-NH-] groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g.
  • a compound of formula (1) wherein L 1 is NH may be converted into the corresponding compound wherein L 1 represents N(R 3 ), in which R 3 is other than
  • alkyl halide R 3 -Hal e.g. iodomethane, cyclopropylmethyl bromide or 1-bromo-3-methoxypropane
  • a base e.g. sodium hydride
  • amine [-NH 2 ] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol, at ambient temperature.
  • a nitro [-NO 2 ] group may be reduced to an amine [-NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium, on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran, or an alcohol, e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • a metal catalyst for example palladium
  • 1 amine [-C ⁇ NH ⁇ groups may be obtained by reduction of nitriles [-CN], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney® nickel, in a solvent such as an ether, e.g. a cyclic ether such as tetrahydrofuran, or an alcohol, e.g. methanol or ethanol, optionally in the presence of ammonia solution at a temperature from ambient to the reflux temperature, or by chemical reduction using for example a metal hydride, e.g. lithium aluminium hydride, in a solvent such as an ether, e.g.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n- butyl- or fert-butyllithium, optionally at a low temperature, e.g. around -78°C, in a solvent ' such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example a lithium base such as n- butyl- or fert-butyllithium
  • a formyl group may be introduced by using ⁇ /, ⁇ /-dimethylformamide as the electrophile; or a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • ⁇ /-Oxides of compounds of formula (1) or (2) may be prepared, for example, by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • R is halogen, e.g.
  • bromo may be converted into the corresponding compound wherein R represents an optionally substituted aryl (e.g. phenyl) or heteroaryl group by treatment with the appropriate aryl or heteroaryl boronic acid in the presence of a transition metal catalyst, e.g. tetrakis(triphenylphosphine)palladium(0).
  • a transition metal catalyst e.g. tetrakis(triphenylphosphine)palladium(0).
  • the reaction is conveniently performed at an elevated temperature in a suitable solvent, e.g. aqueous 1 ,4-dioxane, typically in the presence of a base such as sodium carbonate.
  • Salts of compounds of formula (1 ) or (2) may be prepared by reaction of a compound of formula (1 ) or (2) with an appropriate base or acid in a suitable solvent or mixture of solvents, e.g.
  • salts of compounds of formula (1 ) or (2) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures. Where it is desired to obtain a particular enantiomer of a compound of formula (1 ) or (2) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
  • diastereomeric derivatives e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1 ) or (2), e.g.
  • a racemate and an appropriate chiral compound, e.g. a chiral base.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1 ) or (2) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionisation.
  • Example 3 iV-ri-(Adamantan-1-ylmethyl)piperidin-4-vn-A ⁇ f -(benzoxazol-2-yl)amine Prepared in a similar manner to Example 1 from 2-chlorobenzoxazole [CAS No. 615-18-9] (52 mg) and 1-(adamantan-1-ylmethyl)piperidin-4-ylamine
  • Example 6 iV-ri-(Adamantan-1-ylmethvnpiperidin-4-yl1-)V-(benzothiazol-2-yl)amine Prepared in a similar manner to Example 4 from 2-chlorobenzothiazole [CAS No. 615-20-3] (58 mg) and 1-(adamantan-1-ylmethyl)piperidin-4-ylamine
  • Example 11 lV-ri-((1R,5S)-6,6-DimethylbicvcloF3.1.nhept-2-en-2-ylmethyl)piperidin-4- vn-/V-(6-nitrobenzothiazol-2-yl)amine Prepared in a similar manner to Example 4 from 2-chloro-6- nitrobenzothiazole [CAS No. 2407-11-6] (69 mg) and Intermediate 4 (100 mg).
  • Example 13 /V-n-f(1R,5S)-6,6-Dimethylbicvclor3.1.nhept-2-en-2-ylmethyl)piperidin-4- vH-.V-(6-trifluoromethoxybenzothiazol-2-vDamine
  • 2-chloro-6-trifluoro- methoxybenzothiazole [CAS No. 133840-96-7] (76 mg) and Intermediate 4 (100 mg). Yield 27 mg. M+H 452.
  • TLC R f 0.21 (5% MeOH/DCM).
  • Example 16 ⁇ V-(4-Bromobenzothiazol-2-yl)-V- ⁇ -((1 R.5S)-6.6-dimethyl- bicvclor3.1. ⁇ hept-2-en-2-ylmethyl)piperidin-4-vHamine Prepared in a similar manner to Example 4 from Intermediate 10 (500 mg, 2.0 mmol) and Intermediate 4 (600 mg, 1.98 mmol). Yield 51.0 mg. M+H
  • Example 20 ⁇ V-n-((1R,5S)-6,6-Dimethylbicvclor3.1.nhept-2-en-2-ylmethvnpiperidin-4- vH-/V-(quinolin-2-yl)amine 2-Chloroquinoline (0.611 mmol, 100 mg) was added to a stirred solution of Intermediate 4 (0.611 mmol, 187 mg) and DIPEA (1.833 mmol, 319 mg) in MeCN (2 ml) under an inert atmosphere.
  • Example 33 5-(2-Chlorophenyl)-2- ⁇ -((1S,5R)-6,6-dimethylbicvclor3.1.nhept-2-en-2- ylmethyl)piperidin-4-ylamino1benzothiazole From Example 17 (50 mg, 0.11 mmol) and 2-chlorophenylboronic acid
  • Example 2 (101 mg) was dissolved in DMF (2 ml) under a N 2 atmosphere and NaH (60% in oil, 11.5 mg) was added. The reaction mixture was left to stir for 30 min, then cooled in an ice bath and iodomethane (18 ⁇ l) was added. The mixture was allowed to warm to room temperature and left to stir for 24 hours.
  • Example 42 /V-(6-Chlorobenzothiazol-2-vn-/V- ⁇ -((1 S,5R)-6.6-dimethyl- bicvclof3.1.nhept-2-en-2-ylmethyl)piperidin-4-vn-N-methylamine
  • Example 41 Prepared in a similar manner to Example 41 from Example 19 (100 mg) and iodomethane to give, after purification by preparative HPLC (Method A), the title compound as a colourless gum (41 mg). RT 2.62 minutes. M+H 416.
  • Example 43 ⁇ V-(Benzothiazol-2-vn-/V-(cvclopropylmethvn- ⁇ /- ⁇ -((1S,5R)-6,6-dimethyl- bicvclor3.1. ⁇ hept-2-en-2-ylmethyl)piperidin-4-v ⁇ amine
  • Example 43 From Example 5 (24 mg) and cyclopropylmethyl bromide [CAS No. 7051-34-5] (9 mg) to give, after purification by preparative HPLC (Method A), the title compound (9.2 mg).
  • Example 44V-fBenzothiazol-2-vn- /- ⁇ -((1S,5R -6,6-dimethylbicvclor3.1.1lhept-2-en-2- ylmethyl)piperidin-4-v ⁇ -.V-(3-methoxypropyl)amine Prepared in a similar manner to Example 41 from Example 5 (57 mg) and 1-bromo-3-methoxypropane [CAS No. 36865-41-5] (24 mg) to give, after purification by preparative HPLC (Method A), the title compound (16.7 mg).
  • Chemokine calcium assay The following assay may be used to determine the inhibition of binding of a chemokine to its receptor.
  • CHO cells stably transfected with the human CXCR3 were seeded in a 96-well, black-walled, clear-bottomed tissue culture plate and incubated overnight at 37°C in the presence of 5% CO 2 .
  • the culture medium was gently removed from the well and replaced with wash buffer (Hank's Balanced Salts Solution with 0.2% BSA and 20 mM HEPES pH 7.2) containing 3 ⁇ M Fluo-4 and 0.03% pluronic acid.
  • wash buffer Hank's Balanced Salts Solution with 0.2% BSA and 20 mM HEPES pH 7.2
  • test compounds were dissolved in DMSO and further diluted in wash buffer to give a DMSO concentration of 0.8% (reduced to 0.2% when added to the assay plate in the FLIPRTM).
  • the assay was performed using a FLIPRTM (Molecular Devices). Compound was added to the assay plate after a 10 second baseline. Diluted human recombinant ITAC, IP-10 or MIG was added after a further 2 minutes.
  • Compound activity was calculated as a percentage inhibition of a DMSO solvent control.
  • Compounds of the invention including in particular the compounds of each of the Examples, are able to inhibit the binding of ITAC, IP-10 or MIG to their receptor (CXCR3) with an activity of >50% at 5 ⁇ M.
  • CXCR3 receptor for ITAC
  • CDG receptor for ITAC
  • IP-10 IP-10
  • MIG receptor for ITAC
  • CXCR3 receptor
  • the above assay can also be used to determine the selectivity of the compounds according to the invention, by replacement of CXCR3 with an alternative chemokine receptor such as CCR3 and the use of a chemokine known to bind to such a receptor, such as eotaxin.
  • the compounds of the invention can be shown to be selective inhibitors of CXCR3.
  • the compounds of each of the Examples are at least 5 times more selective with respect to CXCR3 than to other chemokine receptors such as CCR3.

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Abstract

La présente invention concerne une catégorie de dérivés de 4-(benzothiazol-2-ylamino)pipéridine 1-substitués et des composés hétérocycliques associés, qui sont des modulateurs puissants et sélectifs de l'interaction entre CXCR3 et ses ligands de chimiokine, et sont utilisés en conséquence pour le traitement et/ou la prévention d'états pathologiques impliquant le trafic inapproprié des lymphocytes T, y compris les troubles inflammatoires, auto-immuns et immunorégulatoires.
PCT/GB2004/002735 2003-06-28 2004-06-25 Derives heteroaromatiques bicycliques en tant que modulateurs de la fonction cxcr3 WO2005003127A1 (fr)

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WO2006088920A1 (fr) * 2005-02-16 2006-08-24 Schering Corporation Pyridyle a liaison amine et piperazine-piperidines substituees a activite agoniste cxcr3
WO2006088840A1 (fr) * 2005-02-16 2006-08-24 Schering Corporation Nouveaux composes pyridine ou phenyle substitues heterocycliques a activite antagoniste cxcr3
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
WO2007025897A2 (fr) * 2005-09-02 2007-03-08 F. Hoffmann-La Roche Ag Derives de benzooxazole, oxazolopyridine, benzothiazole et thiazolopyridine
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
WO2009017822A3 (fr) * 2007-08-02 2009-04-23 Amgen Inc Modulateur de la pi3 kinase et leurs procédés d'utilisation
US7601844B2 (en) 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
US7820665B2 (en) 2007-12-19 2010-10-26 Amgen Inc. Imidazopyridazine inhibitors of PI3 kinase for cancer treatment
US8299098B2 (en) 2008-06-25 2012-10-30 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9266876B2 (en) 2012-02-02 2016-02-23 Actelion Pharmaceuticals Ltd. 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9951063B2 (en) 2014-03-24 2018-04-24 Idorsia Pharmaceuticals Ltd 8-(piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinoline derivatives
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10047080B2 (en) 2015-01-15 2018-08-14 Idorsia Pharmaceuticals Ltd. (R)-2-methyl-piperazine derivatives as CXCR3 receptor modulators
US10053457B2 (en) 2015-01-15 2018-08-21 Idorsia Pharmaceuticals Ltd. Hydroxyalkyl-piperazine derivatives as CXCR3 receptor modulators
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10259807B2 (en) 2013-07-22 2019-04-16 Idorsia Pharmaceuticals Ltd. 1-(piperazin-1-yl)-2-([1,2,4]triazol-1-yl)-ethanone derivatives

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US7799789B2 (en) 2005-02-16 2010-09-21 Schering Corporation Heterocyclic substituted pyridine or phenyl compounds with CXCR3 antagonist activity
WO2006088840A1 (fr) * 2005-02-16 2006-08-24 Schering Corporation Nouveaux composes pyridine ou phenyle substitues heterocycliques a activite antagoniste cxcr3
JP2008530219A (ja) * 2005-02-16 2008-08-07 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有する、アミン結合ピリジルおよびフェニルで置換されたピペラジン−ピペリジン
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WO2006088920A1 (fr) * 2005-02-16 2006-08-24 Schering Corporation Pyridyle a liaison amine et piperazine-piperidines substituees a activite agoniste cxcr3
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JP4688889B2 (ja) * 2005-02-16 2011-05-25 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有する、アミン結合ピリジルおよびフェニルで置換されたピペラジン−ピペリジン
WO2006129679A1 (fr) 2005-05-31 2006-12-07 Ono Pharmaceutical Co., Ltd. Compose de spiropiperidine et son utilisation medicinale
JP2008545008A (ja) * 2005-06-30 2008-12-11 プロシディオン・リミテッド Ｇｐｃｒアゴニスト
WO2007025897A2 (fr) * 2005-09-02 2007-03-08 F. Hoffmann-La Roche Ag Derives de benzooxazole, oxazolopyridine, benzothiazole et thiazolopyridine
WO2007025897A3 (fr) * 2005-09-02 2007-05-10 Hoffmann La Roche Derives de benzooxazole, oxazolopyridine, benzothiazole et thiazolopyridine
CN101253171B (zh) * 2005-09-02 2011-06-15 霍夫曼-拉罗奇有限公司 苯并噁唑、噁唑并吡啶、苯并噻唑和噻唑并吡啶衍生物
US8609664B2 (en) 2006-01-27 2013-12-17 Bristol-Myers Squibb Co. Piperazinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
US7601844B2 (en) 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7985861B2 (en) 2006-01-27 2011-07-26 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
JP2010535216A (ja) * 2007-08-02 2010-11-18 アムジエン・インコーポレーテツド Ｐｉ３キナーゼ調節剤および使用方法
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WO2009017822A3 (fr) * 2007-08-02 2009-04-23 Amgen Inc Modulateur de la pi3 kinase et leurs procédés d'utilisation
US7820665B2 (en) 2007-12-19 2010-10-26 Amgen Inc. Imidazopyridazine inhibitors of PI3 kinase for cancer treatment
US8299098B2 (en) 2008-06-25 2012-10-30 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US8633226B2 (en) 2008-06-25 2014-01-21 Bristol-Myers Squibb Company Piperidinyl derivative as a modulator of chemokine receptor activity
US9796664B2 (en) 2008-09-03 2017-10-24 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10301323B2 (en) 2011-02-28 2019-05-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
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US9266876B2 (en) 2012-02-02 2016-02-23 Actelion Pharmaceuticals Ltd. 4-(benzoimidazol-2-yl)-thiazole compounds and related aza derivatives
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10428028B2 (en) 2013-03-15 2019-10-01 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10259807B2 (en) 2013-07-22 2019-04-16 Idorsia Pharmaceuticals Ltd. 1-(piperazin-1-yl)-2-([1,2,4]triazol-1-yl)-ethanone derivatives
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